Selective Serotonin Reuptake Inhibitors Paroxetine Research Articles

Irisin ameliorates male sexual dysfunction in paroxetine-treated male rats

Sexual dysfunction is a common clinical condition due to different causes including the use of selective serotonin reuptake inhibitors (SSRI). Especially, SSRI paroxetine is known to cause numerous types of sexual dysfunction in men. There is growing interest in exercise as a non-pharmacological approach for the treatment of SSRI-induced sexual dysfunction. With these in mind, we investigated the effects of irisin, which is a recently detected exercise-linked hormone, on paroxetine-induced sexual dysfunction in male rats. Our findings showed that circulating irisin levels were lower in paroxetine-induced sexual dysfunction in male rats (20 mg/kg/day for 8 weeks by oral gavage than in vehicle-treated rats). In addition, results from sexual behavioral tests revealed that subcutaneous irisin perfusion (100 ng/kg/day via mini-osmotic pumps for 28 days) ameliorated sexual motivation and copulatory performance in sexually impaired male rats treated with paroxetine. The significantly reduced serum testosterone levels and α1-adrenoceptors (ADRA1A) and tyrosine hydroxylase gene (TH) expression levels in the nucleus accumbens (NAc) in paroxetine-induced sexually dysfunctioning male rats were markedly increased following irisin exposure. Similarly, the expression levels of ADRA1A and TH in the medial preoptic area (mPOA) significantly increased in male rats co-administered with paroxetine and irisin compared to the vehicle-treated male rats. These results demonstrate that irisin may be a therapeutic modality that mimics/supports the beneficial effects of exercise for improving SSRI-associated sexual dysfunction in men through increase in serum testosterone levels and increased expression of α1-adrenoceptors and TH in the NAc and mPOA associated with sexual motivation and copulatory behaviors.

Inhibitory effect of the selective serotonin reuptake inhibitor paroxetine on human Kv1.3 channels

Paroxetine is one of the most effective selective serotonin reuptake inhibitors used to treat depressive and panic disorders that reduce the viability of human T lymphocytes, in which Kv1.3 channels are highly expressed. We examined whether paroxetine could modulate human Kv1.3 channels acutely and directly with the aim of understanding the biophysical effects and the underlying mechanisms of the drug. Kv1.3 channel proteins were expressed in Xenopus oocytes. Paroxetine rapidly inhibited the steady-state current and peak current of these channels within 6 min in a concentration-dependent manner; IC50s were 26.3 μM and 53.9 μM, respectively, and these effects were partially reversed by washout, which excluded the possibility of genomic regulation. At the same test voltage, paroxetine blockade of the steady-state currents was higher than that of the peak currents, and the inhibition of the steady-state current increased relative to the degree of depolarization. Paroxetine decreased the inactivation time constant in a concentration-dependent manner, but it did not affect the activation time constant, which resulted in the acceleration of intrinsic inactivation without changing ultrarapid activation. Blockade of Kv1.3 channels by paroxetine exhibited more rapid inhibition at higher activation frequencies showing the use-dependency of the blockade. Overall, these results show that paroxetine directly suppresses human Kv1.3 channels in an open state and accelerates the process of steady-state inactivation; thus, we have revealed a biophysical mechanism for possible acute immunosuppressive effects of paroxetine.

A cross-sectional study of the relationship between CYP2D6 and CYP2C19 variations and depression symptoms, for women taking SSRIs during pregnancy.

Depression during pregnancy affects 10-15% of women, and 5% of women take antidepressants during pregnancy. Clinical guidelines provide recommendations for selective serotonin reuptake inhibitor (SSRI) drug choice and dose based on CYP2D6 and CYP2C19 genotype; however, they are based on evidence from non-pregnant cohorts. This study aimed to test the hypothesis that women with function-altering variants (increased, decreased, or no function) in these pharmacogenes, taking SSRIs prenatally, would have more depression symptoms than women whose pharmacogenetic variants are associated with normal SSRI metabolism. Comprehensive CYP2D6 and CYP2C19 genotyping using a range of methods, including gene copy number analysis, was performed as secondary analyses on two longitudinal cohorts of pregnant women (N= 83) taking the SSRIs paroxetine, citalopram, escitalopram, or sertraline. The Kruskal-Wallis test compared mean depression scores across four predicted metabolizer groups: poor (n= 5), intermediate (n= 10), normal (n= 53), and ultrarapid (n= 15). There were no significant differences between mean depression scores across the four metabolizer groups (H(3) = .73, p= .87, eta-squared = .029, epsilon-squared = .0089). This is the first study of the relationship in pregnancy between CYP2C19 pharmacogenetic variations and depression symptoms in the context of SSRI use. Findings from this initial study do not support the clinical use of pharmacogenetic testing for SSRI use during the second or third trimesters of pregnancy, but these findings should be confirmed in larger cohorts. There is an urgent need for further research to clarify the utility of pharmacogenetic testing for pregnant women, especially as companies offering direct-to-consumer genetic testing expand their marketing efforts.

Visualizing Patterns of Medication Switching Among Major Depressive Patients with Various Stability and Difficulty to Treatments.

IntroductionEfforts have been made in assessing efficacy and tolerability to various antidepressants, but understanding personalized chances of stability to medication switching sequence is still inconclusive. This study aimed to identify naturalistic switching patterns of medication in stratifying MDD patients.MethodsMDD patients were stratified based on treatment difficulty evaluated with the “Treatment Resistance to Antidepressants Evaluation Scale for Unipolar Depression” (TRADES). The duration of the time of diagnoses until the final switch to another class of antidepressants was used as prediction of unstable to drug therapy. ROC analysis was used to determine the cutoff values. A continuous temporal events function from the visual analytic tool was employed to perform patterns of switching between distinct pharmacological class such as selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs).ResultsTRADES scores of 4.5 and not-switching times of 12.5 months were used as cutoff values to divide patients into four subgroups: stable/easy-to-treat (SE), unstable/easy-to-treat (UE), stable/difficult-to-treat (SD) and unstable/difficult-to-treat (UD). A total of 80% and 76.9% of patients initially treated with the SSRIs paroxetine or fluoxetine, respectively, were predicted to be stable to drug therapy. Approximately 70%, 44.8% and 41.4% of patients initially treated with the SNRIs fluvoxamine, sertraline and venlafaxine, respectively, were predicted to be UD, and 60% of patients using duloxetine were predicted to be stable to drug therapy. Analysis of the switching phenomenon showed that SSRIs were the first prescribed medications and mostly taken by the stable subgroups, and SNRIs were the preferentially chosen switching alternative. Medication switching patterns in unstable MDD patients are discussed.ConclusionParoxetine, fluoxetine and duloxetine users were mostly stable among MDD patients in Taiwan with various stability and difficulty to treatments. Although responsiveness to specific medication sequence is likely required for clinical application, the results provide a baseline for such studies.

Pharmacological and Psychoactive Agents for Treatment Resistant Posttraumatic Stress Disorder

The Food and Drug Administration (FDA) approved two selective serotonin reuptake inhibitors (SSRIs) sertraline and paroxetine for the treatment of posttraumatic stress disorder. Many patients do not respond to them and their side effects commonly occur before noticeable therapeutic effects, leading to their discontinuation. Other patients develop treatment resistance to the two approved SSRIs and are treated with other pharmacological agents. A sizable number of patients also do not respond to pharmacological agents and resort to the use of experimental psychoactive agents. This article reviews the definition of treatment resistant posttraumatic stress disorder, and summarizes the various pharmacological and psychoactive agents that have been used for treatment resistant posttraumatic stress disorder including various antidepressants, antipsychotics ,noradrenergic agents, anticonvulsants, mood stabilizers, anxiolytics, hypnotics ,antihistaminergic agents, naltrexone, buprenorphine, D-Cycloserine, neuropeptides, memantine, cannabinoids, 3,4-methylendioxymethamphetamine and ketamine.

Serotonin stimulates Echinococcus multilocularis larval development

BackgroundSerotonin is a phylogenetically ancient molecule that is widely distributed in most metazoans, including flatworms. In addition to its role as a neurotransmitter, serotonin acts as a morphogen and regulates developmental processes. Although several studies have focused on the serotonergic nervous system in parasitic flatworms, little is known on the role of serotonin in flatworm development.MethodsTo study the effects of serotonin on proliferation and development of the cestode Echinococcus multilocularis, we cloned the genes encoding the E. multilocularis serotonin transporter (SERT) and tryptophan hydroxylase (TPH), analyzed gene expression by transcriptome analysis and whole mount in situ hybridization (WMISH) and performed cell culture experiments.ResultsWe first characterized orthologues encoding the SERT and TPH, the rate-limiting enzyme in serotonin biosynthesis. WMISH and transcriptomic analyses indicated that the genes for both SERT and TPH are expressed in the parasite nervous system. Long-term treatment of parasite stem cell cultures with serotonin stimulated development towards the parasite metacestode stage. Mature metacestode vesicles treated with serotonin showed increased rates of incorporation of the thymidine analogue 5-ethynyl-2′-deoxyuridine (EdU), indicating stimulated cell proliferation. In contrast, treatment with the selective serotonin reuptake inhibitor paroxetine strongly affected the viability of parasite cells. Paroxetine also caused structural damage in metacestode vesicles, suggesting that serotonin transport is crucial for the integrity of parasite vesicles.ConclusionsOur results indicate that serotonin plays an important role in E. multilocularis development and proliferation, providing evidence that the E. multilocularis SERT and TPH are expressed in the nervous system of the protoscolex. Our results further suggest that the E. multilocularis SERT has a secondary role outside the nervous system that is essential for parasite integrity and survival. Since serotonin stimulated E. multilocularis metacestode development and proliferation, serotonin might also contribute to the formation and growth of the parasite in the liver.Graphical

PTSD Treatment Literature: Old and Fresh Approaches

PTSD is a brain disorder that exacts large costs to individuals, families, and society in general. Direct monetary costs that are associated with PTSD symptoms of U.S. military veterans have been increasing steadily. Less direct indicators of PTSD costs to society include the externalities of lower economic productivity, family dysfunction, PTSD comorbidities, drug, and alcohol addictions. Veteran awards linked to PTSD are conferred with the tacit assumption that “cures” for PTSD do not exist. Veterans Administration policies adopt the pharmacological strategy of dispensing drugs that have not been approved for PTSD usage by the U.S. Food and Drug Administration. Despite the existing government policies regarding PTSD treatment of veterans, emerging literature indicates that innovative PTSD treatments are available, that they deserve further scrutiny, and that they may present better alternatives to status quo options. In particular, noteworthy research regarding the use of stellate ganglion block or SGB appears to be promising. In addition to SGB research, literature has shown that approaches to PTSD such as physical activity, meditation, wilderness therapy, and self-help hold promise as treatments. Two treatment drugs, the selective serotonin reuptake inhibitor (SSRI) medications sertraline (Zoloft) and paroxetine (Paxil) have been approved by the Food and Drug Administration (FDA) for relieving symptom of PTSD. However, the U.S. Food and Drug Administration warned that these drugs are accompanied with the risk of suicidal thoughts, hostility, and agitation. Equally, if not more troubling, the literature indicates that physicians commonly prescribe benzodiazepine tranquilizers (such as Valium and Xanax) to veterans even though Veterans Administration guidelines advise against their use for PTSD. The Veterans Administration dispensed these drugs to almost a third of veterans being treated for PTSD even though they recognized the need to exercise caution in their use. A review of the literature indicates that PTSD is a growing societal problem; that existing treatments show signs of being problematic, and that innovative treatment strategies deserve greater attention.

Paroxetine Attenuates Cardiac Hypertrophy Via Blocking GRK2 and ADRB1 Interaction in Hypertension.

BackgroundADRB1 (adrenergic receptor beta 1) responds to neuroendocrine stimulations, which have great implications in hypertension. GRK2 (G protein‐coupled receptor kinase 2) is an essential regulator for many G protein‐coupled receptors and subsequent cell signaling cascades, but its role as a regulator of ADRB1 and associated cardiac hypertrophy in hypertension remains to be elucidated.Methods and ResultsIn this study, we found the expressions of GRK2 and ADRB1 in peripheral blood mononuclear cells were positively associated with blood pressure levels in hypertensive patients and with their expression in heart. In vitro evidence showed a direct interaction in ADRB1 and GRK2 and genetic depletion of GRK2 blocks epinephrine‐induced upregulation of hypertrophic and fibrotic genes in cardiomyocytes. Meanwhile, we discovered a selective serotonin reuptake inhibitor paroxetine specifically blockades GRK2 and ADRB1 interaction. In vivo, paroxetine treatment ameliorates hypertension‐induced cardiac hypertrophy, dysfunction, and fibrosis in animal models. We found that paroxetine suppressed sympathetic overdrive and increased the adrenergic receptor sensitivity to catecholamines. Paroxetine treatment also blocks epinephrine‐induced upregulation of hypertrophic and fibrotic genes as well as ADRB1 internalization in cardiomyocytes. Coadministration of paroxetine further potentiates metoprolol‐induced reductions in blood pressure and heart rate, further attenuating cardiac hypertrophy in spontaneously hypertensive rats. Furthermore, in patients with hypertension accompanied with depression, we observed that cardiac remodeling was less severe in those with paroxetine treatment compared with those with other types of anti‐depressive agents.ConclusionsParoxetine promotes ADRB1 sensitivity and attenuates cardiac hypertrophy partially via blocking GRK2‐mediated ADRB1 activation and internalization in the context of hypertension.

G protein-coupled receptor kinase 2 modifies the ability of Caenorhabditis elegans to survive oxidative stress.

Survival and adaptation to oxidative stress is important for many organisms, and these occur through the activation of many different signaling pathways. In this report, we showed that Caenorhabditis (C.) elegans G protein-coupled receptor kinases modified the ability of the organism to resist oxidative stress. In acute oxidative stress studies using juglone, loss-of-function grk-2 mutants were more resistant to oxidative stress compared with loss-of-function grk-1 mutants and the wild-type N2 animals. This effect was Ce-AKT-1 dependent, suggesting that Ce-GRK2 adjusted C. elegans oxidative stress resistance through the IGF/insulin-like signaling (IIS) pathway. Treating C. elegans with a GRK2 inhibitor, the selective serotonin reuptake inhibitor paroxetine, resulted in increased acute oxidative stress resistance compared with another selective serotonin reuptake inhibitor, fluoxetine. In chronic oxidative stress studies with paraquat, both grk-1 and grk-2 mutants had longer lifespan compared with the wild-type N2 animals in stress. In summary, this research showed the importance of both GRKs, especially GRK2, in modifying oxidative stress resistance.

Comparative transcriptomics implicate mitochondrial and neurodevelopmental impairments in larval zebrafish (Danio rerio) exposed to two selective serotonin reuptake inhibitors (SSRIs)

Pharmaceuticals and personal care products are emerging contaminants that are increasingly detected in the environment worldwide. Certain classes of pharmaceuticals, such as selective serotonin reuptake inhibitors (SSRIs), are a major environmental concern due to their widespread use and the fact that these compounds are designed to have biological effects at low doses. A complication in predicting toxic effects of SSRIs in nontarget organisms is that their mechanism of action is not fully understood. To better understand the potential toxic effects of SSRIs, we employed an ultra-low input RNA-sequencing method to identify potential pathways that are affected by early exposure to two SSRIs (fluoxetine and paroxetine). We exposed wildtype zebrafish (Danio rerio) embryos to 100 μg/L of either fluoxetine or paroxetine for 6 days before extracting and sequencing mRNA from individual larval brains. Differential gene expression analysis identified 1550 genes that were significantly affected by SSRI exposure with a core set of 138 genes altered by both SSRIs. Weighted gene co-expression network analysis identified 7 modules of genes whose expression patterns were significantly correlated with SSRI exposure. Functional enrichment analysis of differentially expressed genes as well as network module genes repeatedly identified various terms associated with mitochondrial and neuronal structures, mitochondrial respiration, and neurodevelopmental processes. The enrichment of these terms indicates that toxic effects of SSRI exposure are likely caused by mitochondrial dysfunction and subsequent neurodevelopmental effects. To our knowledge, this is the first effort to study the tissue-specific transcriptomic effects of SSRIs in developing zebrafish, providing specific, high resolution molecular data regarding the sublethal effects of SSRI exposure.

Selective serotonin reuptake inhibitors (SSRIs) prevent meta-iodobenzylguanidine (MIBG) uptake in platelets without affecting neuroblastoma tumor uptake

BackgroundThe therapeutic use of [131I]meta-iodobenzylguanidine ([131I]MIBG) is often accompanied by hematological toxicity, mainly consisting of persistent and severe thrombocytopenia. While MIBG accumulates in neuroblastoma cells via selective uptake by the norepinephrine transporter (NET), the serotonin transporter (SERT) is responsible for cellular uptake of MIBG in platelets. In this study, we have investigated whether pharmacological intervention with selective serotonin reuptake inhibitors (SSRIs) may prevent radiotoxic MIBG uptake in platelets without affecting neuroblastoma tumor uptake.MethodsTo determine the transport kinetics of SERT for [125I]MIBG, HEK293 cells were transfected with SERT and uptake assays were conducted. Next, a panel of seven SSRIs was tested in vitro for their inhibitory potency on the uptake of [125I]MIBG in isolated human platelets and in cultured neuroblastoma cells. We investigated in vivo the efficacy of the four best performing SSRIs on the accumulation of [125I]MIBG in nude mice bearing subcutaneous neuroblastoma xenografts. In ex vivo experiments, the diluted plasma of mice treated with SSRIs was added to isolated human platelets to assess the effect on [125I]MIBG uptake.ResultsSERT performed as a low-affinity transporter of [125I]MIBG in comparison with NET (Km = 9.7 μM and 0.49 μM, respectively). Paroxetine was the most potent uptake inhibitor of both serotonin (IC50 = 0.6 nM) and MIBG (IC50 = 0.2 nM) in platelets. Citalopram was the most selective SERT inhibitor of [125I]MIBG uptake, with high SERT affinity in platelets (IC50 = 7.8 nM) and low NET affinity in neuroblastoma cells (IC50 = 11.940 nM). The in vivo tested SSRIs (citalopram, fluvoxamine, sertraline, and paroxetine) had no effect on [125I]MIBG uptake levels in neuroblastoma xenografts. In contrast, treatment with desipramine, a NET selective inhibitor, resulted in profoundly decreased xenograft [125I]MIBG levels (p < 0.0001). In ex vivo [125I]MIBG uptake experiments, 100- and 34-fold diluted murine plasma of mice treated with citalopram added to isolated human platelets led to a decrease in MIBG uptake of 54–76%, respectively.ConclusionOur study demonstrates for the first time that SSRIs selectively inhibit MIBG uptake in platelets without affecting MIBG accumulation in an in vivo neuroblastoma model. The concomitant application of citalopram during [131I]MIBG therapy seems a promising strategy to prevent thrombocytopenia in neuroblastoma patients.

Paroxetine binding and activation of phosphofructokinase implicates energy metabolism in antidepressant mode of action

Selective serotonin reuptake inhibitors (SSRIs) are the predominant drugs prescribed for Major Depressive Disorder. The immediate pharmacological target of SSRIs is the serotonin transporter. However, the delayed therapeutic effect and high rate of patient non-response make it highly likely that SSRIs also have other molecular targets that are yet to be identified. Cellular thermal shift assay (CETSA) is a method based on thermal stabilization of target proteins upon drug binding. In the present study, we show that the SSRI paroxetine binds to phosphofructokinase (PFK) protein using CETSA. We found that mouse brain PFK and recombinant human PFK proteins are stabilized by paroxetine incubation. Chronic paroxetine treatment also significantly increased mouse brain PFK thermal stability. Paroxetine significantly elevated in vitro and in vivo PFK activity. Levels of several metabolites in glutamate- and energy metabolism-related pathways are significantly correlated with PFK activity in mouse hippocampus. Our data show that paroxetine can bind to PFK and affect its activity. Implications of these results for the antidepressant mode of action of paroxetine are discussed.

Update on pharmacotherapy in psychodermatological disorders

Psychodermatological (PD) conditions encountered in dermatologic practice include primary psychiatric conditions such as delusions of parasitosis or secondary psychiatric conditions such as anxiety and depression due to dermatologic disease. The psychotropics include antipsychotic agents, anti-anxiety agents, antidepressants, and miscellaneous drugs such as anti convulsants. Anti psychotics are further divided into first-generation and second-generation drugs. Currently, second-generation drugs e.g., risperidone are preferred over first-generation drugs e.g., pimozide in delusional infestation owing to the side effect profile of the latter. Anti-anxiety agents include benzodiazepines used in acute anxiety and buspirone in chronic anxiety disorders. They are frequently prescribed along with antidepressants. Although dependence and necessity of tapering is a problem with benzodiazepines, delayed onset of action is a feature of buspirone. The commonly used antidepressants in dermatology include selective serotonin reuptake inhibitors (citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline), selective serotonin norepinephrine reuptake inhibitors (venlafaxine, desvenlefaxine, and duloxetine), norepinephrine dopamine reuptake inhibitors (bupropion), tricyclic antidepressants (doxepin, amitriptyline, imipramine, and clomipramine), and tetracyclic antidepressants (mirtazapine). Miscellaneous drugs include anticonvulsants such as gabapentin and pregabalin, naltrexone, and N-acetyl cysteine. The principles of PD treatment are first establish the psychiatric diagnosis, followed by initiating drug treatment. The choice of drugs is dependent on multiple factors such as side-effect profile, drug interactions, and co-morbid conditions. Usually, drugs are started at a low dose and gradually increased. A literature search was done in Pubmed, Google Scholar, and Medline databases, and articles on treatment were analyzed.

Peripheral microvascular serotoninergic signaling is dysregulated in young adults with major depressive disorder.

Dysfunction of the brain serotonergic system is implicated in the pathogenesis of major depressive disorder (MDD). Serotonin is also a vasoactive signaling molecule, the effects of which are modulated by both nitric oxide (NO) and the serotonin transporter [the primary target of selective serotonin reuptake inhibitors (SSRIs)]. Despite its role in the neurobiology of depression, serotoninergic signaling mechanisms in the microvasculature of adults with MDD are unknown. We hypothesized that 1) cutaneous microvascular responsiveness to serotonin would be attenuated in MDD and mediated by reductions in both 2) NO-dependent and 3) serotonin reuptake-dependent mechanisms. In 12 adults with MDD (nonmedicated) and 12 nondepressed adults, red cell flux (laser-Doppler flowmetry) was measured during graded intradermal microdialysis perfusion of 1) serotonin (10-10 to 10-1 mol/L) alone and in combination with a nonselective NO synthase inhibitor NG-nitro-l-arginine methyl ester (l-NAME; 15 mmol/L) and the SSRI paroxetine (10 μmol/L); and 2) paroxetine (n = 6; 10-9 to 10-2 M) alone and in combination with l-NAME. Serotonin-induced vasodilation was preserved in MDD. The NO-dependent component of serotonin-induced vasodilation was not different between groups. Paroxetine augmented vasodilatory responsiveness to serotonin via NO-dependent mechanisms in both groups; however, the magnitude was blunted in MDD. The NO contribution to direct paroxetine-induced vasodilation was also reduced in adults with MDD. Collectively, these preliminary data suggest that cutaneous microvascular serotoninergic signaling is dysregulated in adults with MDD and mediated by NO-dependent and serotonin reuptake-dependent mechanisms, providing initial mechanistic insight to the purported vasculoprotective effect of chronic SSRI treatment.NEW & NOTEWORTHY Cutaneous microvascular vasodilatory responsiveness to serotonin was preserved in adults with major depressive disorder (MDD). However, the contribution of serotonin reuptake-dependent mechanisms to serotonin-induced dilation was reduced in MDD. Direct perfusion of the selective serotonin reuptake inhibitor (SSRI) paroxetine elicited vasodilation that is partially mediated by nitric oxide (NO)-dependent mechanisms, but these responses were blunted in MDD, reflective of a diminished contribution of NO to the direct effects of a SSRI on the cutaneous microvasculature.

Treatment of Post-Stroke Depression.

This review presents a critical appraisal of current therapeutic strategies for patients with post-stroke depression (PSD). We present the reader with the most recent evidence to support pharmacological, psychosocial, and neuromodulation interventions in PSD. We also discuss the relevance of using antidepressants and psychotherapy to prevent PSD and discuss evidence that antidepressant treatment may reduce mortality after stroke. Neuroinflammation and decrease neurogenesis and plasticity may play an important role in the mechanism of PSD. The strongest predictors of PSD are stroke severity, early physical disability, and severity of loss of functioning. Nevertheless, populations at risk for PSD are yet to be identified. Recent meta-analysis examined the efficacy of pharmacotherapy and psychotherapy. There is consensus that antidepressants such as escitalopram and paroxetine produce a significantly greater response and remission rate of PSD than placebo. Randomised controlled trials (RCTs) using psychotherapy are fewer, but recent meta-analysis tend to suggest efficacy for this treatment modality. Neuromodulation using repetitive transcranial magnetic stimulation (rTMS) or transcranial direct current stimulation (tDCS), as well as novel psychosocial interventions are potentially useful treatments in need of further research. Pharmacological therapy with antidepressants and psychotherapy should be considered as first line of treatment for PSD. The most effective antidepressants are the selective serotonin reuptake inhibitors escitalopram and paroxetine, whereas cognitive behavioural therapy is the most effective psychotherapeutic intervention.

Baseline Serum Levels of Beclin-1, but Not Inflammatory Factors, May Predict Antidepressant Treatment Response in Chinese Han Patients With MDD: A Preliminary Study.

Currently, the choice of medical treatment for major depressive disorder (MDD) is primarily based on a trial-and-error process. Thus, identification of individual factors capable of predicting treatment response is of great clinical relevance. Recent work points towards beclin-1 and inflammatory factors as potential biomarkers of antidepressant treatment response. The primary aim of the study was to investigate whether pre-treatment serum levels of beclin-1 and inflammatory factors could predict antidepressant treatment response in Chinese Han patients with MDD. Forty patients with MDD were treated with either a selective serotonin reuptake inhibitor (SSRI) (paroxetine in 20 cases) or a serotonin–norepinephrine reuptake inhibitor (SNRI) (duloxetine in 13 cases and venlafaxine in 7 cases). Depression scores and serum levels of beclin-1 were measured at the baseline and after 8 weeks of antidepressant treatment. Serum C-reactive protein (CRP), interleukin (IL)-1B, and IL-6 levels were determined using enzyme-linked immunosorbent assay kits at the baseline. Twenty-seven patients were identified as treatment responders, whereas 13 were identified as non-responders after 8 weeks of antidepressant treatment. Baseline serum beclin-1 levels were significantly higher in non-responders than in responders (p = 0.001), whereas no differences were found in baseline serum CRP, IL-1B, or IL-6 levels between responders and non-responders. There were no significant correlations between baseline levels of beclin-1 and baseline IL-1β, IL-6, and CRP levels—neither in the total sample nor in responder and non-responder groups. Moreover, logistic regression models and a random forest model showed that baseline serum beclin-1, but not inflammatory factors, was an independent and the most important predictor for antidepressant treatment response. Furthermore, serum beclin-1 levels were significantly increased in responders (p = 0.027) but not in non-responders after 8 weeks of treatment (p = 0.221). Baseline serum beclin-1 levels may be a predictive biomarker of antidepressant response in patients with MDD. Moreover, beclin-1 may be involved in the therapeutic effect of antidepressant drugs.

Perinatal exposure to the SSRI paroxetine alters the methylome landscape of the developing dentate gyrus.

Evidence in humans and rodents suggests that perinatal exposure to selective serotonin reuptake inhibitor (SSRI) antidepressants can have serious long-term consequences in offspring exposed in utero or infancy via breast milk. In spite of this, there is limited knowledge of how perinatal SSRI exposure impacts brain development and adult behaviour. Children exposed to SSRIs in utero exhibit increased internalizing behaviour and abnormal social behaviour between the ages of 3 and 6, and increased risk of depression in adolescence; however, the neurobiological changes underlying this behaviour are poorly understood. In rodents, perinatal SSRI exposure perturbs hippocampal gene expression and alters adult emotional behaviour (including increased depression-like behaviour). The present study demonstrates that perinatal exposure to the SSRI paroxetine leads to DNA hypomethylation and reduces DNA methyltransferase 3a (Dnmt3a) mRNA expression in the hippocampus during the second and third weeks of life. Next-generation sequencing identified numerous differentially methylated genomic regions, including altered methylation and transcription of several dendritogenesis-related genes. We then tested the hypothesis that transiently decreasing Dnmt3a expression in the early postnatal hippocampus would mimic the behavioural effects of perinatal SSRI exposure. We found that siRNA-mediated knockdown of Dnmt3a in the dentate gyrus during the second to third week of life produced greater depression-like behaviour in adult female (but not male) offspring, akin to the behavioural consequences of perinatal SSRI exposure. Overall, these data suggest that perinatal SSRI exposure may increase depression-like behaviours, at least in part, through reduced Dnmt3a expression in the developing hippocampus.

Enhanced availability of serotonin increases activation of unfatigued muscle but exacerbates central fatigue during prolonged sustained contractions.

Animal preparations have revealed that moderate synaptic release of serotonin (5-HT) onto motoneurones enhances motor activity via activation of 5-HT2 receptors, whereas intense release of 5-HT causes spillover of 5-HT to extrasynaptic 5-HT1A receptors on the axon initial segment to reduce motoneurone activity. We explored if increasing extracellular concentrations of endogenously released 5-HT (via the selective serotonin reuptake inhibitor paroxetine) influences the ability to perform unfatigued and fatigued maximal voluntary contractions in humans. Following the ingestion of paroxetine, voluntary muscle activation and torque generation increased during brief unfatigued maximal contractions. In contrast, the ability to generate maximal torque with increased 5-HT availability was compromised under fatigued conditions, which was consistent with paroxetine-induced reductions in motoneurone excitability and voluntary muscle activation. This is the first in vivo human study to provide evidence that 5-HT released onto the motoneurones could play a role in central fatigue. Brief stimulation of the raphe-spinal pathway in the turtle spinal cord releases serotonin (5-HT) onto motoneurones to enhance excitability. However, intense release of 5-HT via prolonged stimulation results in 5-HT spillover to the motoneurone axon initial segment to activate inhibitory 5-HT1A receptors, thus providing a potential spinal mechanism for exercise-induced central fatigue. We examined how increased extracellular concentrations of 5-HT affect the ability to perform brief, as well as sustained, maximal voluntary contractions (MVCs) in humans. Paroxetine was used to enhance 5-HT concentrations by reuptake inhibition, and three studies were performed. Study 1 (n= 14) revealed that 5-HT reuptake inhibition caused an ∼4% increase in elbow flexion MVC. However, when maximal contractions were sustained, time-to-task failure was reduced and self-perceived fatigue was higher with enhanced availability of 5-HT. Study 2 (n= 11) used twitch interpolation to reveal that 5-HT-based changes in motor performance had a neural basis. Enhanced 5-HT availability increased voluntary activation for the unfatigued biceps brachii and decreased voluntary activation of the biceps brachii by 2-5% following repeated maximal elbow flexions. The final study (n= 8) investigated whether altered motoneurone excitability may contribute to 5-HT changes in voluntary activation. F-waves of the abductor digiti minimi (ADM) were unaffected by paroxetine for unfatigued muscle and marginally affected following a brief 2-s MVC. However, F-wave area and persistence were significantly decreased following a prolonged 60-s MVC of the ADM. Overall, high serotonergic drive provides a spinal mechanism by which higher concentrations of 5-HT may contribute to central fatigue.

Cumulative Antidepressant Use and Risk of Dementia in a Prospective Cohort Study.

To determine whether antidepressant use is associated with dementia risk. Prospective cohort study. Kaiser Permanente Washington (KPWA), an integrated healthcare delivery system. Community-dwelling individuals aged 65 and older without dementia and with 10 years or more of KPWA enrollment at baseline (N=3,059). Primary exposures were selective serotonin reuptake inhibitors (paroxetine vs other), tricyclic antidepressants, and serotonin antagonist and reuptake inhibitors. Using health plan pharmacy data, we calculated cumulative medication exposure, defined as total standardized daily doses (TSDDs), over rolling 10-year windows. Exposure in the most recent year was excluded to avoid use related to prodromal symptoms. The Cognitive Abilities Screening Instrument was administered every 2 years; low scores triggered clinical evaluation and consensus diagnosis procedures. Dementia risk was estimated according to medication use using Cox proportional hazards models. During a mean follow-up of 7.7 years, 775 participants (25%) developed dementia; 659 (22%) developed possible or probable Alzheimer's disease. Individual antidepressant classes were not associated with differences in dementia risk, although paroxetine use was associated with higher risk of dementia for all TSDD categories than no use (0-90 TSDDs: hazard ratio (HR)=1.69, 95% confidence interval (CI)=1.18-2.42; 91-365 TSDDs: HR=1.40, 95% CI=0.88-2.23; 366-1095 TSDDs: HR=2.13, 95% CI=1.32-3.43; ≥1095 TSDDs: HR=1.42, 95% CI=0.82-2.46). Most commonly prescribed nonanticholinergic depression medications used in late life do not appear to be associated with dementia risk. Paroxetine and other anticholinergic antidepressants may be exceptions in older individuals. Future studies are warranted to improve scientific understanding of potential associations in other settings and populations.

Interactions of Selective Serotonin Reuptake Inhibitors with β-Amyloid.

Treating Alzheimer's disease (AD) is a major challenge at the moment with no new drugs available to cure this devastating neurodegenerative disorder. In this regard, drug repurposing, which aims to determine novel therapeutic usage for drugs already approved by the regulatory agencies, is a pragmatic approach to discover novel treatment strategies. Selective serotonin reuptake inhibitors (SSRIs) are a known class of United States Food and Drug Administration approved drugs used in the treatment of depression. We investigated the ability of SSRIs fluvoxamine, fluoxetine, paroxetine, sertraline, and escitalopram on Aβ42 aggregation and fibrillogenesis. Remarkably, the aggregation kinetic experiments carried out demonstrate the anti-Aβ42 aggregation activity of SSRIs fluoxetine, paroxetine, and sertraline at all the tested concentrations (1, 10, 50, and 100 μM). Both fluoxetine and paroxetine were identified as the most promising SSRIs, showing 74.8 and 76% inhibition of Aβ42 aggregation at 100 μM. The transmission electron microscopy experiments and dot-blot study also demonstrate the ability of fluoxetine and paroxetine to prevent Aβ42 aggregation and fibrillogenesis, providing further evidence. Investigating the binding interactions of fluoxetine and paroxetine in the Aβ42 oligomer and fibril models derived from the solid-state NMR structure suggests that these SSRIs interact at a region close to the N-terminal (Lys16-Glu22) in the S-shaped cross-β-strand assembly and reduce Aβ42 fibrillogenesis. On the basis of this study, a pharmacophore model is proposed which shows that the minimum structural requirements to design novel Aβ42 aggregation inhibitors include the presence of one ionizable group, one hydrophobic group, two aromatic rings, and two hydrogen bond donor groups. These studies demonstrate that SSRIs have the potential to prevent Aβ42 aggregation by direct binding and could be beneficial to AD patients on SSRIs.